Highly Diastereodivergent Synthesis of Tetrasubstituted Cyclohexanes Catalyzed by Modularly Designed Organocatalysts

Abstract

A highly diastereodivergent synthesis of tetrasubstituted cyclohexanes has been achieved using modularly designed organocatalysts (MDOs) which are self‐assembled in situ from amino acids and cinchona alkaloid derivatives. Diastereodivergence is realized through controlling the stereoselectivity of the individual steps of a tandem Michael/Michael reaction. Up to 8 of the 16 possible stereoisomers have been successfully obtained in high stereoselectivities using MDOs for the tandem reaction and an ensuing epimerization. The method was used in the enantioselective synthesis of the natural products (−)‐α‐ and β‐lycoranes.

Recent Progress in Organocatalytic Asymmetric Domino Transformations

“…It was also verified experimentally that none of the individual modules could catalyze this domino reaction. The utility of this methodology was further demonstrated in the synthesis of two natural products (−)‐β‐lycorane ( 765 ) and (−)‐α‐lycorane ( 766 ) (Scheme ) …”

“…Thus, diastereodivergent catalysis can be readily achieved with the MDOs. For example, we realized a diastereodivergent synthesisof 8 of the 16 possible stereoisomers of tetrasubstituted cyclohexanals ( 760 – 763 and their enantiomers) from the same substrates ( 76 and 541 ) in high diastereo‐ and enantioselectivities using MDOs self‐assembled from the enantiomers of proline [( S )‐ 764 or ( R )‐ 764 ] and the Cinchona alkaloid thiourea derivatives 447 or 438 (Scheme ) . The 1,2‐ syn ‐diastereomers 760 and 761 were formed via a domino Michael/Michael reaction by using the MDOs 447 /( S )‐ 764 and 438 /( S )‐ 764 at room temperature (Conditions A ), respectively, whereas their enantiomers were obtained by using the pseudo‐enantiomeric MDOs 438 /( R )‐ 764 and 447 /( R )‐ 764 under similar conditions, respectively (Scheme ).…”

Advances in Asymmetric Diastereodivergent Catalysis

“…Our group is interested in designing and applying modularly designed organocatalysts (MDOs), which are formed in situ in the reaction media through the self‐assembly of predesigned catalyst modules, in organocatalytic reactions . Exploiting the pseudo‐diastereomeric nature of the MDOs self‐assembled from amino acid and Cinchona alkaloid derivatives, we realized a highly diastereodivergent synthesis of tetrasubstituted cyclohexane derivatives with four contiguous stereogenic centers via a tandem Michael/Michael reaction in 2014 . Our working hypothesis was that the stereochemical outcome of each step of the tandem reaction could be separately controlled by the amino acid and Cinchona alkaloid moieties of the MDOs, such that different diastereomeric products could be obtained through a simple permutation of the two components of the MDOs.…”

Stereoselective Synthesis of 3‐Oxabicyclo[3.3.1]Nonan‐2‐Ones via a Domino Reaction Catalyzed by Modularly Designed Organocatalysts

“…[4c] The reaction produced the tetrahydropyran derivative 4 in a good yield and an excellent ee value. [4c] Our group is interested in developing novel diastereodivergent catalytic methods [5,6] using the modularly designed organocatalysts (MDOs), [7] which are self-assembled in the reaction media from cinchona alkaloid derivatives and amino acids. Inspired by Ma's work, [4c] we envisioned that a domino Michaelhemiacetalization-oxa-Michael reaction between 1 a and (E)-7-oxo-7-phenylhept-5-enal (5 a) catalyzed by MDOs should lead to the formation of the pyranopyran derivative 6 (Scheme 1, middle equation) and, based on our earlier results, [5] potentially diastereodivergence could also be achieved during the product formation by using appropriate MDOs.…”